Recent work has suggested that physical forces transmitted to the site of bone repair significantly influences the spatial distribution and temporal cascade of gene expression, and subsequent cell and tissue differentiation during regeneration. Despite these presumed mechano-biologic relationships and substantial experimental observations, the specific cellular and molecular events associated with the reception and response to biophysical forces remains incompletely characterized. The purpose of this research project is to investigate the mechanoresponsive cells that are involved in the fracture repair process and determine the potential regulatory role of physical forces alone or in concert with a variety of biofactors in enhancing bone regeneration. Utilizing rat models and specialized fracture fixation devices, controlled micro displacements will be applied to fractures crated in femoral diaphyseal bone. We will particularly focus on determining the cell populations that are the sensors and responders to physical forces as a function of time. In addition, using an in situ tissue engineering approach to express local biofactors, we will explore the potential synergistic mechanisms of biologic and biomechanical stimuli. The results of this work may provide us with new insights about the regulators of fracture repair. These insights may lead to the development of new strategies for increasing the rate in which fractures heal and increasing the quality of healing. This might significantly improve healthcare delivery for fractures and reduce work time lost.